ES2382513B2 - Dialysis solution containing at least one CCR2 antagonist - Google Patents

Abstract

Dialysis solution containing at least one CCR2 antagonist. # The invention relates to a sterile aqueous solution for peritoneal dialysis comprising one or more CCR2 antagonists, electrolytes and one or more osmotic agents for the treatment of patients with renal failure. undergoing peritoneal dialysis. In this way the solution fulfills the function of dialysis solutions, in addition to reducing the ultrafiltration deficit and deterioration of the peritoneal membrane caused by exposure to dialysis solutions.

Description

Dialysis solution containing at least one CCR2 antagonist

Background

Peritoneal dialysis is a kidney replacement therapy, where the peritoneal membrane is used as a dialysis membrane. This technique consists in the administration in the peritoneal cavity of a hyperosmotic solution, which generates an osmotic gradient between the blood and the peritoneal cavity, through the peritoneal membrane. This removes excess fluid and metabolites for the peritoneal cavity. After a period the dialysis solution is replaced by a new one.

Patients treated with peritoneal dialysis have the same survival as hemodialysis patients. It can be done at home or at work by the patient himself, without the need to go to the hospital. In addition, peritoneal dialysis is cheaper than hemodialysis.

Due to the quality, effectiveness and price ratio, peritoneal dialysis should be widely used. However, only 10% of world patients with renal insufficiency are treated with peritoneal dialysis. This can be explained by the fact that continuous exposure to dialysis solutions lead to deterioration of the peritoneal membrane and loss of dialysate function.

The most used osmotic agent is glucose, because it is cheap and safe. Conventional dialysis solutions have high concentrations of glucose and the products of glucose degradation (GDP), lactate and low pH are irritating to the peritoneal membrane and have negative effects at the systemic level. At the local level, exposure to dialysis solutions reduces the viability of mesothelial cells, induces mesenchymal epithelial transition of mesothelial cells, causes impaired migration of immune system cells, low-grade inflammation, angiogenesis and fibrosis, leading to thickening of peritoneal membrane. These morphological alterations of the peritoneal membrane lead to the partial loss of the dialysate function, which causes the transfer of the patient for hemodialysis. In addition, at a systemic level, the partial loss of the dialysate function of the peritoneal membrane leads to greater glucose absorption, which will affect its nutritional status, and fluid retention, which leads to cardiac overload and increased cardiovascular risk (García - López, E et al Nature Rev. Nephrol., 2012; doi: 10.1038 / nrneph.2012.13).

Great efforts are being made to improve the biocompatibility of dialysis solutions. In this sense, the substitution of glucose as an osmotic agent is sought, and thus decrease the levels of GDP. Dialysis solutions whose osmotic agents are amino acids (solutions without GDP) or icodextrin (solution with low levels of GDP) are currently being marketed. The absence or decrease in GDP makes these solutions more physiological. However, some inconveniences prevent its use as the only dialysis solution, having to be alternated with glucose solutions. The solution with amino acids has less osmotic power than glucose and was developed for daily exchange in poorly nourished patients. In addition to the high cost, its continued use can lead to an increase in uremia and acidosis. Icodextrin is absorbed more slowly than glucose being recommended for long exchanges and for patients with ultrafiltration failure. However, the accumulation of circulating icodextrin metabolites, the increased risk of aseptic peritonitis and allergies restrict their use only to a daily exchange.

Peritoneal dialysis solutions that use glucose as an osmotic agent have also improved their biocompatibility. This is thanks to the use of systems with more than one chamber to separate the buffer from glucose that has allowed the reduction of the GDP concentration and the use of pH close to neutrality in the latest generation solutions. These new dialysis solutions are more physiological, improving the viability of the peritoneal membrane, causing less in fl ammation and improving peritoneal immunity. In animal models, solutions with low GDP concentration induce lower VEGF production suggesting lower angiogenesis. By these characteristics these are considered biocompatible solutions. However, it is not clear that the use of low-GDP solutions increases patient survival or therapy (García-López, E et al Nature Rev. Nephrol (2012); doi: 10.1038 / nrneph.2012.13). The use of biocompatible peritoneal dialysis solutions implies an increase in the costs of therapy, limiting access to these dialysis solutions in the poorest countries.

Biocompatible solutions are not without problems. The use of solutions with low GDP levels and neutral pH is related to an early ultrafiltration deficit, which is transitory. Patients treated with liquids low in GDP have greater transport of small solutes and lower ultrafiltration (Bajo, MA et al Nephrol Dial Transplant, 2011, 26: 282-291; Fernández-Perpén, A et al Perit. Dial. Int. Doi: 10.3747 /pdi. 2010.00315). With this the therapy does not work well, causing greater glucose absorption and fluid accumulation by the patient. Patients in whom the ultrafiltration deficit is severe are transferred to conventional solutions or to hemodialysis. The mechanisms involved in the development of the early ultrafiltration deficit are still unclear, but it is known to be independent of angiogenesis.

Exposure to dialysis solutions leads to the synthesis of various chemokines in the peritoneal cavity. One of these chemokines is CCL2, which is involved in the recruitment and activation of monocytes and macrophages to the site of inflammation. Its action is mediated by the interaction with the receptor, CCR2, present in the membrane of these cells. This chemicin is not the only one responsible for the migration of these cells, but it seems to be the most important.

On the one hand, the attraction of macrophages enhances inflammation and immunity, which prevents infection. On the other hand, macrophages recruited to the sites of inflammation secrete large amounts of TGF-β that causes fibrosis. In experimental models of kidney fibrosis Kang YS, et al, Kidney Int. 2010; 78: 883-94; Kitagawa K, et al, Am J Pathol. 2004; 16: 237-46), liver (Karlmark KR, et al, Hepatology. 2009 Jul; 50 (1): 261-74) and heart (Xu J, et al, Am J Physiol Heart Circ Physiol. 2011 301: H538- 47), treatment with CCR2 antagonists prevents macrophage migration, reducing the local synthesis of TGF-β and preventing the development of fibrosis. Interestingly, it is known that new dialysis solutions facilitate macrophage migration to the peritoneal cavity and reduce peritoneal fibrosis.

CCR2 signaling appears to promote angiogenesis, through the recruitment of endothelial cells and smooth muscle cells. CCR2 antagonist has been shown to have tumor growth inhibitory effect by inhibiting angiogenesis. In this way, inhibition of CCR2 signaling can prevent the formation of new vessels.

Conventional dialysis solutions, as well as the latest generation, have deficiencies that can compromise both the therapy and the quality of life and the patient's own life. Therefore, it is necessary to develop new peritoneal dialysis solutions that solve or improve the deficiencies of the state of the art. Several attempts have sought to improve ultrafiltration or prevent peritoneal membrane deterioration (JP4379636; USP 6214802; USP 6342500; USP 6753341; USP 6803363; WO 00/53013; WO 201107630 A1). In the present invention, a new peritoneal dialysis solution has been developed that improves or prevents the deficiencies of the other solutions described in the prior art, prolonging the time of stay of patients in PD and subsequently their quality of life.

Description of the invention

The invention relates to a sterile aqueous solution for peritoneal dialysis comprising one or more CCR2 antagonists, electrolytes and one or more osmotic agents for the treatment of patients with renal failure undergoing peritoneal dialysis. In this way the solution fulfills the function of dialysis solutions, in addition to reducing the ultrafiltration deficit and deterioration of the peritoneal membrane caused by exposure to dialysis solutions.

Therefore, an essential aspect of the present invention refers to a solution for peritoneal dialysis comprising the following elements:

to)

Water

b)

electrolytes

C)

buffer solution

d)

osmotic agent

and)

CCR2 antagonist.

In a preferred embodiment, the Na +, K +, Mg2 +, Ca2 +, Cl- electrolytes of different salts or any combination thereof. Where the concentration of electrolytes varies between:

a) Na 50-200 mmol / l

b) K 0-4 mmol / l

c) Mg 0-2 mmol / l

d) Ca 0.5-3 mmol / l

e) Cl 50-200 mmol / l.

In another preferred embodiment, the buffer solution may be lactate, bicarbonate, the combination thereof or Lhistidine.

In another preferred embodiment, the osmotic agent of the peritoneal dialysis solution, used to remove excess fluid and metabolites from the blood is selected from glucose, glucose polymer, mannitol, glycerol, amino acids, peptides, polypeptides, albumin or any combination. of them with osmolarity between 100 and 700 mosm / l.

In another preferred embodiment, CCR2 antagonists used in the dialysis solution are selected from organic germanium compounds such as propagermanium, spirogermanium and 3-Oxigermilpropionic acid polymer.

Another preferred embodiment, CCR2 antagonists used in the dialysis solution are selected from CCR2 blocking peptides and CCR2 blocking antibodies or organic and inorganic compounds that prevent signaling via CCR2.

Another essential aspect of the present invention refers to the use of the dialysis solution for the preparation of a medicament.

One embodiment refers to the use of the dialysis solution for the preparation of a medicament for the prevention and / or treatment of kidney diseases.

One embodiment refers to the use of the dialysis solution for the preparation of a medicament for the prevention and / or treatment of kidney diseases.

Another preferred embodiment refers to the use of the dialysis solution for the preparation of a medicament for the prevention and / or treatment of the ultrafiltration deficit.

Another preferred embodiment refers to the use of the dialysis solution for the preparation of a medicament for the prevention and / or treatment of the high transport of the peritoneal membrane.

Another preferred embodiment refers to the use of the dialysis solution for the preparation of a medicament for the prevention and / or treatment of peritoneal membrane deterioration.

Another preferred embodiment refers to the use of the dialysis solution for the preparation of a medicament for the prevention and / or treatment of thickening of the peritoneal membrane.

Another preferred embodiment refers to the use of the dialysis solution for the preparation of a medicament for the prevention and / or treatment of renal insufficiency.

The dialysis solution of the present invention is administered one to four times a day in a volume of 1 to 3 liters per dose. The solution is administered to patients suffering from renal insufficiency according to the methods normally used to perform peritoneal dialysis.

Brief description of the fi gures

Figure 1 describes the ultrafiltration deficit associated with biocompatible solutions.

Figure 2 describes the inverse correlation between the number of peritoneal cells and the ultrafiltration deficit.

Figure 3 describes the effect of the CCR2 antagonist on the ultrafiltration deficit in animals treated with solutions with low levels of GDP and physiological pH.

Figure 4 describes the effect of the CCR2 antagonist on the thickening of the peritoneal membrane after 30 days of exposure to conventional dialysis solution.

Figure 5 describes the effect of the CCR2 antagonist on the number of macrophages in the peritoneal cavity of mice exposed to dialysis solutions.

Examples of embodiment of the invention

The following examples illustrate the present invention. However, these examples are not limiting. They are informative and in no case limited to the methodologies used, which can be altered in order to achieve similar results.

Example

Exposure model of the mouse peritoneal membrane to peritoneal dialysis solutions

Non-uremic, female C57BL / 6j mice, 12 to 16 weeks old, were purchased from Charles River (Barcelona) and kept in a conventional animal farm. Through microsurgery, a catheter with a subcutaneous port (minute mice port, Access Technologies, Skokie, IL) was installed in the peritoneal cavity of the mice, as described previously (González-Mateo, GT, Perit Dial Int. 2009 ; 29: 227-30). The dialysis solution (2 ml) is instilled in the peritoneal cavity through the subcutaneous port every day of the experiment. We use three types of dialysis solutions that have characteristics of the marketed solutions. Dialysis solution 1 (SD1) corresponds to a conventional solution with low pH and high levels of GDP. The SD2 and SD3 solutions are biocompatible with low levels of GDP and physiological pH. The difference between SD2 and SD3 is the buffer used. SD2 uses lactate while SD3 the buffer is bicarbonate. The characteristics of the solutions are presented in the table below.

Determination of ultrafiltration and CCL2 in peritoneal fluid

After 15 days of exposure to the different dialysis solutions, all mice receive an instillation of 2 ml of SD1. Forty minutes later the mouse is sacrificed and all the liquid is recovered from the peritoneal cavity to determine the volume. The greater the volume recovered, the better the ultrafiltration capacity of the peritoneal membrane.

The peritoneal fluid was divided into small samples and staked at -80 ° C. Subsequently, the concentration of CCL2 was determined by flow cytometry using the FlowCytomix technique (Bender MedSystems GmbH).

Determination of peritoneal membrane deterioration

The deterioration of the peritoneal membrane was determined by the thickening of the peritoneal membrane. To do this, after 30 days of exposure to the dialysis solution, the mice were sacrificed and a peritoneal membrane biopsy was fixed in Bouin's solution and embedded in paraffin. Biopsies were cut at 5 μm and stained with hematoxylin and eosin. The thickness of the peritoneal membrane was determined by microscopy, using Leica CTR6000 microscope (Leica Microsystems Heidelberg, Germany) with the LAS-AF6000 image analysis program. The measure of each individual was determined by the median of the measurements obtained at every 50 μm.

CCR2 antagonists

In the experiments we used propagermanium and RS504393 as CCR2 antagonists.

Propagermanium and RS504393 were diluted in commercial solution so that in 2 ml of the solution it would provide a dose of 5 mg / kg and 4 mg / kg, respectively. The solution with CCR2 antagonist was used daily.

Data collection and analysis

Each experiment was performed with at least five mice per group. The results were expressed in graphs of boxes and mustaches where the three quartiles and the minimum and maximum data values are represented. For the analysis of the dice we use the non-parametric Mann-Whitney U test.

For the correlation study we use Spearman's correlation. All analyzes were performed using Prism 4 (GraphPad Software, Inc., La Jolla, USA).

Results

The use of biocompatible solutions is related to an early ultrafiltration deficit that has a tendency to recover over time (Bajo, MA et al, Nephrol Dial Transplant (2011) 26: 282-291; Fernández-Perpén, A et al, Perit Dial Int. (2012); doi: 10.3747 / pdi. 2010.00315). We analyze the effect, in a short period of time (15 days), of treatment with conventional solutions SD1 (bioincompativel) and with low levels of GDP (SD2 and SD3, plus biocompativeis) on early ultrafiltration (Figure 1). Mice treated with SD2 tend to have lower ultrafiltration than mice treated with SD1 (P = 0.056). On the other hand, mice treated with SD3 have an ultrafiltration deficit on day 15 of treatment (P <0.01).

The drained volume of the peritoneal cavity of the mice exposed to the different dialysis solutions correlates inversely with the number of drained cells (Figure 2) (Spearman's r = -0.712; P = 0.0029).

The addition of propagermanium to SD3 prevents the early ultrafiltration deficit (Figure 3).

However, the number of peritoneal cells among animals treated with SD3 or SD3 plus propagermanium did not show differences (P = 0.29).

The conventional dialysis solution promotes peritoneal membrane deterioration, characterized by thickening. In the long term, conventional dialysis solutions with CCR2 antagonists (SD1 + propagermanium; SD1 + RS504393) have better preservation of the peritoneal membrane than mice treated with just conventional solutions (SD1) (Figure 4). Mice treated with SD1 and CCR2 antagonists were less thick than those treated only with SD1.

The macrophage in the peritoneal cavity plays a role in the prevention of peritonitis. The solution with CCR2 antagonist does not prevent macrophage migration to the peritoneal cavity, preserving the immune response capacity (Figure 5). Each group of animals had at least ten mice.

Claims (14)

1. Dialysis solution containing at least one CCR2 antagonist comprising the following elements:

to)

Water

b)

electrolytes

b)

buffer solution

C)

at least one osmotic agent

d)

at least one CCR2 antagonist.

2.

Dialysis solution containing at least one CCR2 antagonist according to claim 1, wherein the electrolytes are selected from the following group consisting of: the Na +, K +, Mg2 +, Ca2 +, Cl− electrolytes or any combination thereof.

3.

Dialysis solution containing at least one CCR2 antagonist according to claim 2, wherein each electrolyte has the following concentration range: Na 50-200 mmol / l; K 0-4 mmol / l; Mg 0-2 mmol / l; Ca 0.5-3 mmol / l; Cl 50-200 mmol / l.

Four.

Dialysis solution containing at least one CCR2 antagonist according to claims 1-3, wherein the buffer solution is selected from lactate, bicarbonate, the combination thereof or L-histidine in the appropriate concentration.

5.

Dialysis solution containing at least one CCR2 antagonist according to claims 1 to 4, wherein the osmotic agent is selected from the group consisting of glucose, glucose polymer, mannitol, glycerol, amino acids, peptides, polypeptides, albumin or any combination of the same with osmolarity between 100 and 700 mosm / l.

6.

Dialysis solution containing at least one CCR2 antagonist according to claims 1 to 5, wherein the CCR2 antagonist is selected from organic germanium compounds such as propagermanium, spirogermanium and 3-Oxigermilpropionic acid polymer.

7.

Dialysis solution containing at least one CCR2 antagonist according to claim 6, wherein the concentration of organic germanium compounds has a concentration between 0.5 mg / kg and 50 mg / kg.

8.

Dialysis solution containing at least one CCR2 antagonist according to claims 1 to 5, wherein the CCR2 antagonist is selected from CCR2 blocking peptides, CCR2 blocking antibodies or organic and inorganic compounds that prevent signaling via CCR2, at concentrations that generate The same effect.

9.

Use of the dialysis solution containing at least one CCR2 antagonist for the preparation of a medicine.

10.

Use of the dialysis solution containing at least one CCR2 antagonist for the preparation of a medicament for the prevention and / or treatment of kidney diseases.

eleven.

Use of the dialysis solution containing at least one CCR2 antagonist for the preparation of a medicament for the prevention and / or treatment of the ultrafiltration deficit.

12.

Use of the dialysis solution containing at least one CCR2 antagonist for the preparation of a medicament for the prevention and / or treatment of peritoneal membrane deterioration.

13.

Use of the dialysis solution containing at least one CCR2 antagonist for the preparation of a medicament for the prevention and / or treatment of ultrafiltration failure.

SPANISH OFFICE OF THE PATENTS AND BRAND Application no .: 201200477 SPAIN Date of submission of the application: 07.05.2012 Priority Date: REPORT ON THE STATE OF THE TECHNIQUE 51 Int. Cl.: A61P13 / 12 (2006.01) A61K9 / 08 (2006.01) RELEVANT DOCUMENTS

Category

56 Documents cited Claims Affected

TO

YOUNG SUN KANG ET AL “Novel C-C chemokine receptor 2 antagonists in metabolic disease: a review of recent developments” EXPERT OPIN. INVESTIG. DRUGS vol. 20, 2011, pages 745756. Page 751. 1-13

TO

YOUNG SUN KANG ET AL “CCR2 antagonism improves insulin resistance, lipid metabolism, and diabetic nephropathy in type 2 diabetic mice” KIDNEY INTERNATIONAL, vol. 78, 2010, pages 883-894. Pages 887-891. 1-13

TO

SATOSHI KOKUBO ET AL “Activation of p38 mitogen-activated protein kinase promote peritoneal fibrosis by regulating fibrocytes” PERITONEAL DIALYSIS INTERNATIONAL, vol.32, no. 1, January 2012, pages 10-19. Pages 10, 11, 16 and 18. 1-13

TO

US 2012/0101069 A1 (MOEDDEL ET AL) 26.04.2012, Paragraph [0002] and claim 9. 1-13

TO

US 2009/0258906 A1 (HACHTEL ET AL.) 15.10.2009, Paragraph [0392]. 1-13

Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application

This report has been prepared • for all claims • for claims no:

Date of realization of the report 25.05.2012

Examiner S. González Peñalba Page 1/5

REPORT OF THE STATE OF THE TECHNIQUE Application number: 201200477 Minimum documentation sought (classification system followed by classification symbols) A61P, A61K Electronic databases consulted during the search (name of the database and, if possible, terms of search used) INVENES, EPODOC, WPI, NPL, BIOSIS, MEDLINE, EMBASE, XPESP State of the Art Report Page 2/5  WRITTEN OPINION Application number: 201200477 Date of Completion of Written Opinion: 05.25.2012 Statement

Novelty (Art. 6.1 LP 11/1986)

Claims Claims 1-13 IF NOT

Inventive activity (Art. 8.1 LP11 / 1986)

Claims Claims 1-13 IF NOT

The application is considered to comply with the industrial application requirement. This requirement was evaluated during the formal and technical examination phase of the application (Article 31.2 Law 11/1986).  Opinion Base.- This opinion has been made on the basis of the patent application as published. State of the Art Report Page 3/5  WRITTEN OPINION Application number: 201200477 1. Documents considered.- The documents belonging to the state of the art taken into consideration for the realization of this opinion are listed below.

Document

Publication or Identification Number publication date

D01

YOUNG SUN KANG ET AL “Novel C-C chemokine receptor 2 antagonists in metabolic disease: a review of recent developments” EXPERT OPIN. INVESTIG. DRUGS vol. 20, 2011, pages 745-756. Page 751.

D02

YOUNG SUN KANG ET AL “CCR2 antagonism improves insulin resistance, lipid metabolism, and diabetic nephropathy in type 2 diabetic mice” KIDNEY INTERNATIONAL, vol. 78, 2010, pages 883-894. Pages 887-891.

D03

SATOSHI KOKUBO ET AL “Activation of p38 mitogen-activated protein kinase promote peritoneal fibrosis by regulating fibrocytes” PERITONEAL DIALYSIS INTERNATIONAL, vol.32, no. 1, January 2012, pages 10-19. Pages 10, 11, 16 and 18.

D04

US 2012/0101069 A1 (MOEDDEL et al) 04.24.2012

D05

US 2009/0258906 A1 (HACHTEL et al.) 15.10.2009

2. Statement motivated according to articles 29.6 and 29.7 of the Regulations for the execution of Law 11/1986, of March 20, on Patents on novelty and inventive activity; quotes and explanations in support of this statement The present patent application, as it has been written, refers to a dialysis solution comprising at least one CCR2 antagonist (CCL2 chemokine receptor), water, electrolytes, buffer solution and an osmotic agent (claim 1) . The electrolytes are selected from Na +, K +, Mg 2+, Ca 2+, Cl- or combinations thereof (claim 2), with a range of concentrations that vary according to the selected electrolyte (claim 3). As the buffer solution, lactate, bicarbonate, or L-histidine can be used (claim 4). The osmotic agent is selected from glucose, glucose polymer, mannitol, glycerol etc (claim 5). The CCR2 antagonist can be selected from among organic germanium compounds (claim 6) at a concentration between 0.5 mg / kg and 50 mg / kg (claim 7), CCR2 blocking peptides, CCR2 blocking antibodies or organic compounds and inorganic that prevent signaling via CCR2 (claim 8). And finally, the use of said dialysis solution is also claimed for the preparation of a medicament (claim 9) for the prevention and / or treatment of renal diseases (claim 10), of ultrafiltration deficit (claim 11), of the deterioration of the peritoneal membrane (claim 12) and ultrafiltration failure (claim 13). NOVELTY AND INVENTIVE ACTIVITY ARTS. 6 AND 8 OF THE LP Document D01 refers to CCR2 receptor antagonists, for certain metabolic diseases particularly for obesity and related systemic complications. Various CCR2 inhibitors appear in this document, among which RS-504393 can be highlighted (see Table 2). RS-504393 has been described as a CCR2 antagonist that has a high binding affinity for CCR2. This drug improves renal interstitial fobrosis. It also reduces the expression of TGF-� pro-inflammatory markers, and macrophage infiltration (see page 751). Document D02 studies the effect of a CCR2 antagonist, specifically RS504393, on insulin resistance and diabetic nephropathy. Treatment with CCR2 antagonists suppresses the expression of profibrotic or proinflammatory molecules in the kidney (see page 887-891). Document D03 makes reference to the fact that the p38MAPK pathway (p38 mitogen-activated protein kinase) regulates the production of chemokines, which has been shown to contribute to the development of fibrosis, which is associated with the ultrafiltration deficit and the failure of the ability to dialysis (see page 10). Fibrocytes express chemokine receptors (for example CCR2) which are involved in fibrosis formation. Recent studies have shown that p38MAPK phosphorylation is essential for the production of various chemokines (CCL2) and for the translation signals of chemokine receptors such as CCR2 (see page 11). Pharmacological inhibition of p38MAPK signaling reduces the extent of fibrosis (page 16). Infiltration of fibrocytes in diseased organs has been shown to be regulated by chemokine receptor-chemokine systems (including CCL2 and its CCR2 receptor). It has been shown that inhibition of the CCR2-CCL2 system reduces fibrocyte infiltration and severity of fibrosis In the present study, blocking p38MAPK signaling reduces the number of fibrocytes expressing CCR2, in relation to CCL2 expression and the intensity of peritoneal fibrosis, suggesting that the CCR2-CCL2 system depends on p38MAPK ( see page 18). State of the Art Report Page 4/5  WRITTEN OPINION Application number: 201200477 Document D04 deals with solutions for hemodialysis and / or peritoneal dialysis comprising creatine compounds. The purpose of these solutions is to significantly reduce the high concentrations of glucose normally contained in peritoneal dialysis solutions and which lead to peritoneal fibrosis and induction of type II diabetes (see paragraph [0002]). Such solutions contain creatine compounds, water, Na, K, Ca, Mg, Cl, glucose, bicarbonate ions and buffer solution (see claim 9). Document D05 describes compounds of formula I as antagonists of CCR2 receptors. The document also refers to the use of said compounds to treat different diseases, among other peritonitis associated with peritoneal dialysis (see paragraph [0392]). Therefore, none of the documents cited, considered alone or in combination, reveals the dialysis solution of the present invention. Nor, in said documents cited there are suggestions that direct the person skilled in the art towards the invention defined in claims 1-13, whereby the object of claims 1-13 meets the requirement of novelty and inventive activity in accordance with the Articles 6 and 8 of the LP. State of the Art Report Page 5/5